Generation and targeting of human tumor-specific Tc1 and Th1 cells transduced with a lentivirus containing a chimeric immunoglobulin T-cell receptor

Cancer Res. 2004 Feb 15;64(4):1490-5. doi: 10.1158/0008-5472.can-03-2780.

Abstract

CD4+ Th cells, in particular IFN-gamma-producing Th1 cells, play a critical role in the activation and maintenance of Tc1 cells that are essential for tumor eradication. Here, we report the generation of artificial tumor-specific Th1 and Tc1 cells from nonspecifically activated T cells using a lentiviral transduction system. Anti-CD3-activated T cells from healthy human donors were transduced with a lentivirus containing a chimeric immunoglobulin T-cell receptor gene composed of single-chain variable fragments derived from an anticarcinoembryonic antigen (CEA)-specific monoclonal antibody fused to an intracellular signaling domain derived from the cytoplasmic portions of membrane-bound CD28 and CD3zeta. These artificial tumor-specific Tc1 and Th1 cells, termed Tc1- and Th1-T bodies, respectively, could be targeted to CEA+ tumor cells independently of MHC restriction. Specifically, Tc1-T bodies demonstrated high cytotoxicity and produced IFN-gamma in response to CEA+ tumor cell lines but not CEA- tumors. Although Th1-T bodies exhibited low cytotoxicity, they secreted high levels of IFN-gamma and interleukin-2 in response to CEA+ tumor cells. Such CEA+ tumor-specific activation was not observed in mock gene-transduced nonspecific Tc1 and Th1 cells. Moreover, Tc1- and Th1-T bodies exhibited strong antitumor activities against CEA+ human lung cancer cells implanted into RAG2(-/-) mice. Furthermore, combined therapy with Tc1- and Th1-T bodies resulted in enhanced antitumor activities in vivo. Taken together, our findings demonstrate that Tc1- and Th1-T bodies represent a promising alternative to current methods for the development of effective adoptive immunotherapies.

MeSH terms

  • Animals
  • Carcinoembryonic Antigen / immunology
  • Cell Line, Tumor
  • Cytokines / biosynthesis
  • Humans
  • Immunoglobulins / genetics*
  • Immunotherapy, Adoptive*
  • Interferon-gamma / biosynthesis
  • Lentivirus / genetics
  • Mice
  • Mice, Inbred BALB C
  • Neoplasms / therapy*
  • Receptors, Antigen, T-Cell / genetics*
  • Recombinant Fusion Proteins / genetics*
  • T-Lymphocytes, Cytotoxic / immunology*
  • Th1 Cells / immunology*
  • Transduction, Genetic

Substances

  • Carcinoembryonic Antigen
  • Cytokines
  • Immunoglobulins
  • Receptors, Antigen, T-Cell
  • Recombinant Fusion Proteins
  • Interferon-gamma